Melanins are heteropolymers derived from the spontaneous polymerization of intermediates formed during the enzymatic or chemical oxidation of L-tyrosine and other phenolic molecules, or the autooxidation of L-dopa and similar catecholes. (See Blois, "The Melanins: Their Synthesis and Structure" in Photochemical and Photobiological Reviews, Vol. 3, pages 115-135, 1978; Lerner, Advances, in Neurology, 5 211-223, 1974; and Duff, et al., Biochemistry, 27::7112-7116, 1988.) Natural melanins occur as pigments in hair, skin, irides of the eye, and substantia nigra and locus ceruleus of the brain. The known biological functions of natural melanins derive from their diverse coloration, their ability to absorb ultraviolet radiation, and their electron transfer properties.
The various colors of melanins depend, in large part, on the initial substrate. Existing terminology follows this approach to classification. Brown and black melanins originating from L-tyrosine and L-dopa are termed "eumelanins", while yellow and red melanins which contain sulfhydryl compounds are termed "pheomelanins" (Prota, 1980, cited above). Eumelanin and pheomelanin biosyntheses occur in specialized organelles of melanocytes called melanosomes (Seiji, M., et al., Nature (London) 197:1082-1084, 1963), and they become water-insoluble melanin granules.
Neuromelanins are found in the cytoplasm of catecholamine-producing neurons (Bazelton, M., et al., Neurol 17:512-519, 1967), and can be synthesized from L-dopa, dopamine, norepinephrine, epinephrine, and 5-hydroxytryptamine (Blois, 1978, and Lerner, 1974, both cited above). In the brain the neuromelanins primarily are present in water-insoluble forms.
The melanins of particular interest for the purpose of this invention are water-soluble forms of eumelanins, neuromelanins and pheomelanins. These forms of melanins can be prepared from known starting materials such as L-dopa, L-tyrosine, etc. (See Arnow, Science, 87:308, 1938; and Debing, et al., Molecular Pharm., 33:470-476, 1988.)
Melanins are also known to bind certain chloroquine and phenothiazine antibiotics, which may account for the toxicity of these antibiotics in tissues with high melanin content (Lindquist, N.G., Upsala J. Med. Sci. 91:283-288, 1986; and Larsson, et al., Biochem. Pharmacol. 28:1181-1187, 1979). Electrostatic forces involving anionic sites on melanins presumably carboxyl groups) appear to be important to the antibiotic affinity of melanins (Larsson, et al., cited above). As far as is known, however, there have been no reports of melanins displaying any antiviral or antibacterial activity.
Human immunodeficiency virus (HIV) is the etiologic agent of Acquired Immune Deficiency Syndrome (AIDS). This lentivirus infects CD4.sup.+ cells causing their direct or indirect destruction (Lifsun, et al., Science 232:1123-1127, 1986); Siliciano, et al., Cell 54:561-575, 1988). As a consequence of CD4.sup.+ cell depletion, the host becomes susceptible to opportunistic infections and neoplasms. Several drugs have been identified which inhibit the replication of this virus in vitro (Haseltine, W.A., J. Acquir. Immune Def. Syndr., 2:311-324, 1989) but only 3'-azidothymidine (AZT) has received general acceptance for clinical use. The proven clinical efficacy of AZT is limited, and its use is restricted by toxicity and drug-resistant forms of the virus. Therefore, new antiviral agents are urgently needed.
The problem of treating patients infected with human immunodeficiency virus is that the viruses which cause AIDS have serological subtypes. The most prevalent form of HIV is designated HIV-1, and a less prevalent subgroup is HIV-2. (Popovic, et al., Science 224:497-500, 1984; Hahn, et al., PNAS 82:4813-4817, 1985; and Clavel, et al., Nature 324: 691-695, 1986.) It is desired to find an agent which is effective for controlling or inhibiting all forms of HIV.